Exploiting tumor lineage features for precision cancer therapy

Cancer cells often retain lineage- and tissue of origin-specific programs established prior to malignant transformation. This observation has been elaborated by advances in single-cell and lineage-tracing technologies, which provide high-resolution mapping of these features. Here, we provide an overview of these recent technological developments and examine how the tissue of origin shapes tumor behavior and vulnerabilities. We discuss how the preferential selection of oncogenic drivers by specific tissues leads to distinct genetic alterations across cancers. We then explore the continued dependence of cancer cells on lineage-specific physiological functions and signaling pathways, thereby revealing lineage-dependent therapeutic targets. Finally, we highlight how lineage-specific cell surface marker expression informs precision immunotherapies. Together, these insights are driving a shift toward therapies tailored to the developmental and functional identities of cancer cells.